纳米雄黄肾毒性的代谢组学研究

Metabolic profiling of the nephrotoxicity of realgar nanoparticles in rats

采用色谱-质谱联用的代谢组学方法分析纳米雄黄对大鼠肾脏中内源性小分子代谢物的影响,研究代谢物谱变化与肾毒性之间的关联性,为纳米雄黄毒性机制的深入研究、纳米雄黄药物的临床应用提供依据。将SD大鼠随机分为溶媒对照组、雄黄低中高剂量组和纳米雄黄低中高剂量组(40,200,1 000 mg/kg)共7组,连续灌胃28 d后处死大鼠,收集血清和肾脏样本。经血生化和组织病理学检查,证实纳米雄黄可导致肾脏损伤,且受损程度呈剂量依赖性。同时采用LC-MS和GC-MS对肾脏中代谢物变化进行整体表征,利用模式识别进行数据挖掘,发现高剂量纳米雄黄组大鼠肾脏样本中半胱氨酸、蛋氨酸、脯氨酸及LysoPE、LysoPC等32个代谢物含量较对照组均发生明显改变,提示上述代谢物与纳米雄黄肾毒性相关,为潜在毒性标志物。代谢通路分析结果表明,纳米雄黄对肾脏的毒性机制可能与氨基酸和脂质代谢等有关。

The effect of realgar nanoparticles（NPs）on endogenous small molecules in rat kidney was analyzed by mass spectrometry-based metabolomics. The relationship between the changes of metabolites and the nephrotoxicity of realgar NPs was also discussed to provide a basis for the further toxicity study and the clinical application of realgar NPs. SD rats were randomly divided into seven groups, including control group, three doses（40, 200, 1 000 mg/kg）of relegar and realgar NPs groups, respectly. After 28 days of continuous intragastric administration, all rats were sacrificed and their serum and kidney samples were collected. The toxic effect of realgar NPs on kidney tissues were examined by biochemical analysis and histopathologic examination, which revealed a dose-dependent nephrotoxicity induced by realgar NPs. The LC-MS and GC-MS analysis were performed for the subsequent metabolomics study. A series of 32 metabolites were found to be altered significantly in the kindey of realgar NPs treated rats, and might serve as potential nephrotoxicity biomarkers. The results of metabolic pathway analysis indicated that the nephrotoxicity of realgar NPs might be associated with the disorders of the amino acids and phosphatidic acid metabolism.